Ocular Drug Delivery System Presented By

Mahajan Pratik Shivram

M.Pharm (II Semister)

Department of Pharmaceutics, R. C. Patel Institute of Pharmaceutical

Education & Research, Shirpur04/15/2023 1

Introduction Anatomy and physiology of the eye Mechanism of ocular absorption Physicochemical factor influencing corneal absorption

of drug Mechanism of controlled drug release into eye Approaches to improve ocular drug delivery Different drug delivery systems for ocular therapy Classification of ocular drug delivery systems Evaluation of ocular drug delivery system References

CONTENTS

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Definition : They are specialized dosage forms designed to be instilled onto the external surface of the eye (topical), administered inside (intraocular) or adjacent (periocular ) to the eye or used in conjunction with an ophthalmic device.

The most commonly employed ophthalmic dosage forms are solutions, suspensions, and ointments.

But these preparations when in stilled into the eye are rapidly drained away from the ocular cavity due to tear flow and lacrimal nasal drainage.

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INTRODUCTION

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Ocular administration of drug is primarily associated with the need to treat ophthalmic diseases.

Eye is the most easily accessible site for topical administration of a medication.

Ideal ophthalmic drug delivery must be able to sustain the drug release and to remain in the vicinity of front of the eye for prolong period of time.

The newest dosage forms for ophthalmic drug delivery are: gels, gel-forming solutions, ocular inserts, intravitral injections and implants.

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INTRODUCTION

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ANATOMY AND PHYSIOLOGY OF THE EYE

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Corneal routes: Maximum absorption takes place through the cornea, which leads the drug into aueous humor.

Non corneal routes: The non-corneal route involves absorption across the sclera and conjunctiva ,this route is not productive as it retrains the entry of drug into intraocular tissue.

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MECHANISM OF DRUG ABSORPTON IN THE EYE

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1) Partition coefficient : Lipophilic drugs absorbed better than hydrophilic drugs across the cornea. The more hydrophilic the drug, the more resistant is the epithelium to penetration,

whereas the stroma and endothelium are limited in their resistance .

2) Molecular size : Cellular pores and intracellular spaces may be important for the transportation of

hydrophilic compound .

3) Charge : The corneal epithelial barrier is highly selective for the absorption of positively

charged solutes, due to coulombic attraction between the negatively charged corneal

epithelial surface and the positively charged drug molecule.

4) pKa of the drug : Due to extensive dilution by lacrimal fluid, the pH of the vehicle becomes more or

less equal to the lacrimal fluid. Hence, it is only the pKa of the drug that determines

its ocular penetrability.7

PHYSICOCHEMICAL FACTOR INFLUENCING CORNEAL ABSORPTION OF DRUG

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The mechanism of controlled drug release into the eye is as follows:

1) Diffusion: In the Diffusion mechanism, the drug is released continuously at a controlled rate

through the membrane into the tear fluid. The release of drug can take place via diffusion through the pores. Controlled release can be further regulated by gradual dissolution of solid

dispersed drug within this matrix as a result of inward diffusion of aqueous

solutions. In a soluble device, true dissolution occurs mainly through polymer swelling. In swelling-controlled devices, the active agent is homogeneously dispersed in a

glassy polymer. Since glassy polymers are essentially drug impermeable, no

diffusion through the dry matrix occurs.

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MECHANISM OF CONTROLLED DRUG RELEASE INTO EYE

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When the insert is placed in the eye, water from the tear fluid begins to penetrate the matrix, then swelling and consequently polymer chain relaxation and drug diffusion take place.

The dissolution of the matrix, which follows the swelling process, depends on polymer structure: linear amorphous polymers dissolve much faster than cross-linked or partially crystalline polymers.

2) Osmosis: In the Osmosis mechanism, the insert comprises a transverse impermeable

elastic membrane dividing the interior of the insert into a first compartment and a second compartment.

the first compartment is bounded by a semi-permeable membrane and the impermeable elastic membrane.

second compartment is bounded by an impermeable material and the elastic membrane. There is a drug release aperture in the impermeable wall of the insert.

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MECHANISM OF CONTROLLED DRUG RELEASE INTO EYE

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The first compartment contains a solute which cannot pass through the semi-permeable membrane and the second compartment provides a reservoir for the drug which again is in liquid or gel form.

When the insert is placed in the aqueous environment of the eye, water diffuses into the first compartment and stretches the elastic membrane to expand the first compartment and contract the second compartment so that the drug is forced through the drug release aperture.

3) Bioerosion: In the Bioerosion mechanism, the configuration of the body of the insert is

constituted from a matrix of bioerodible material in which the drug is dispersed.

Contact of the insert with tear fluid results in controlled sustained release of the drug by bioerosion of the matrix.

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MECHANISM OF CONTROLLED DRUG RELEASE INTO EYE

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1. Viscosity enhancers 2. Eye ointments3. Gel 4. Penetration enhancers 5. Liposomes 6. Niosomes 7. Nanosuspension 8. Microemulsion9. Nanoparticles

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APPROACHES TO IMPROVE OCULAR DRUG DELIVERY SYSTEM

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LIQUIDS

Solutions

Suspensions

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Classification Of Ocular Drug Delivery Systems

SOLID

Ocular inserts

Contact lenses

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OCULAR DELIVERY SYSTEMS

CONVENTIONAL NOVEL

CONTROLLED PARTICULATE

o IMPLANTS o INSERTo DENDRIMERSo IONTOPORESISo COLLAGEN SHIELDo CONTACT LENSESo MICROEMULSIONSo NANO SUSPENSION

o MICROPARTICLSo NANOPARTICLS

o LIPOSOMESo NIOSOMESo PHARMACOSOMES

o SOLUTIONo SUSPENSIONo EMULSIONo OINTMENTo GELS

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DIFFERENT DRUD DELIVERY SYSTEM FOR OCULAR THERAPY

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OCULAR INSERTS

NONERODABLEOCUSERT

ERODABLESODI

COLLAGEN SHIELDS

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OCUFIT SR

OCULAR INSERT

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1) Solution: Today most of the topical ophthalmic preparations are in the form of

aqueous solutions. A sterile homogeneous solution dosage form have many advantages over

the other dosage such as formulation, including the easily commercially capability produce on large scale manufacture.

There are various factors that must be consider during the formulating aqueous solution includes selection of appropriate salt of the drug, solubility in solvents, therapeutic systemic effect, ocular toxicology, pKa of formulation, and the effect of pH of the formulation.

Others stability parameters includes such as solubility, tonicity, viscosity, buffering capacity, compatibility with formulation ingredients and effect of packaging components, choice of appropriate preservative, ocular comfort and dosing administration

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CONVENTIONAL DRUG DELIVERY SYSTEM FOR OCULAR THERAPY

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2) Suspension: Ophthalmic suspensions products is another part of the ocular drug

delivery system and have many distinct advantages over others formulation.

Recently developed drugs are generally hydrophobic poor solubility in water and aqueous medium. Formulation offers a sterile, preserved, effective, stable and pharmaceutically elegant.

The formulation of a ophthalmic suspension many problem occurred such a non homogenecity of the dosage form, settling of particles, cake formation, aggregation of the suspended particles.

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CONVENTIONAL DRUG DELIVERY SYSTEM FOR OCULAR THERAPY

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3) Ointment: Prolongation of drug contact time with the external ocular surface can be

achieved using ophthalmic ointment vehicle. The ointment base is sterilized by heat and appropriately filtered while

molten to remove foreign particulate matter.

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Ointment base is sterilized by heat and filtered while molten

to remove foreign particulate matter.

It is then placed into a sterile steam jacketed

to maintain the ointment in a molten state and excipients

are added

The entire ointment may be passed

through a previously sterilized colloid mill

CONVENTIONAL DRUG DELIVERY SYSTEM FOR OCULAR THERAPY

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4) Gels:

Ophthalmic gels are composed of mucoadhesive polymers that provide

localized delivery of an active ingredient to the eye. Such polymers have a

property known as bioadhesion.

These polymers are able to extend the contact time of the drug with the

biological tissues and there by improve ocular bioavailability.

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CONVENTIONAL DRUG DELIVERY SYSTEM FOR OCULAR THERAPY

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1) Liposomes: Liposomes are biocompatible and biodegradable lipid vesicles made up of

natural lipids and about 25 –5000 nm in diameter. They are having an intimate contact with the corneal and conjunctival surfaces

which is desirable for drugs that are poorly absorbed, the drugs with low

partition coefficient, poor solubility or those with medium to high molecular

weights and thus increases the probability of ocular drug absorption. Vesicle composed of phospholipids bilayer enclosing aqueous compartment in

alternate fashion. It is Biodegradable, Non-toxic in nature. Polar drugs are incorporated in aqueous compartment while lipophilic drugs are

intercalated into the liposome membrane.

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NOVEL DRUG DELIVERY SYSTEM FOR OCULAR THERAPY

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2) Niosomes: The major limitations of liposomes are chemical instability, oxidative

degradation of phospholipids, cost and purity of natural phospholipids.

To avoid this niosomes are developed as they are chemically stable as

compared to liposomes and can entrap both hydrophobic and hydrophilic drugs.

They are non toxic and do not require special handling techniques.

Niosomes are nonionic surfactant vesicles that have potential applications in

the delivery of hydrophobic or amphiphilic drugs.

3) Pharmacosomes: This term is used for pure drug vesicles formed by the amphiphilic

drugs. The amphiphilic prodrug is converted to pharmacosomes on dilution

with water. Since many drugs are also amphiphiles, they can form the vesicles. 20

NOVEL DRUG DELIVERY SYSTEM FOR OCULAR THERAPY

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1) Implants:

Implants have been widely employed to extend the release of drugs in ocular fluids and tissues particularly in the posterior segment.

Implants can be broadly classified into two categories based on their

degradation properties:

(1) Biodegradable

(2) Nonbiodegradable

With implants, the delivery rate could be modulated by varying polymer

composition.

Implants can be solids, semisolids or particulate-based delivery systems.21

CONTROLLED DRUG DELIVERY SYSTEM FOR OCULAR THERAPY

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2) Contact lens:

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CONTROLLED DRUG DELIVERY SYSTEM FOR OCULAR THERAPY

Contact lenses can be a way of providing extended

release of drugs into the eye.

Conventional hydrogel soft contact lenses have the

ability to absorb some drugs and release them into the

post lens lachrymal fluid, minimizing clearance and

sorption through the conjunctiva.

Their ability to be a drug reservoir strongly depends on

the water content and thickness of the lens, the molecular

weight of the drug, the concentration of the drug loading

solution and the time the lens remains in it. 04/15/2023

3) Iontophoresis: In Iontophoresis direct current drives ions into cells or tissues. For

iontophoresis the ions of importance should be charged molecules of the

drug.

If the drug molecules carry a positive charge, they are driven into the tissues at

the anode; if negatively charged, at the cathode.

Requires a mild electric current which is applied to enhance ionized drug

penetration into tissue.

Ocular iontophoresis offers a drug delivery system that is fast, painless, safe,

and results in the delivery of a high concentration of the drug to a specific site.

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CONTROLLED DRUG DELIVERY SYSTEM FOR OCULAR THERAPY

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3) Iontophoresis: Ocular iontophoresis delivery is not only fast, painless and safe but it

can also deliver high concentration of the drug to a specific site.

Ocular iontophoresis has gained significant interest recently due to its

non-invasive nature of delivery to both anterior and posterior segment.

Iontophoretic application of antibiotics may enhance their bactericidal

activity and reduce the severity of disease

Can overcome the potential side effects associated with intraocular

injections and implants.

Iontophoresis is useful for the treatment of bacterial keratitis.

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CONTROLLED DRUG DELIVERY SYSTEM FOR OCULAR THERAPY

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4) Insert:

1) Non Erodible Insert

Ocusert

The Ocusert therapeutic system is a flat, flexible,

elliptical device designed to be placed in the inferior

cul-de-sac between the sclera and the eyelid and to

release Pilocarpine continuously at a steady rate for 7

days.

The device consists of 3 layers…..

1. Outer layer - ethylene vinyl acetate copolymer layer.

2. Inner Core - Pilocarpine gelled with alginate main

polymer.

3. A retaining ring - of EVA impregnated with titanium

di oxide

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CONTROLLED DRUG DELIVERY SYSTEM FOR OCULAR THERAPY

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2) Erodible Insert

The solid inserts absorb the aqueous tear fluid and gradually erode or disintegrate.

The drug is slowly leached from the hydrophilic matrix.

They quickly lose their solid integrity and are squeezed out of the eye with eye

movement and blinking.

Do not have to be removed at the end of their use.

Three types :

1. Lacriserts

2. Sodi

3. Minidisc

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CONTROLLED DRUG DELIVERY SYSTEM FOR OCULAR THERAPY

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2) Erodible Insert1) Lacriserts: Sterile rod shaped device made up

of hydroxyl propyl cellulose without any preservative.

For the treatment of dry eye syndromes.

It weighs 5 mg and measures 1.27 mm in diameter with a length of 3.5 mm.

It is inserted into the inferior fornix.

2) Sodi: Soluble ocular drug inserts. Small oval wafer. Sterile thin film of oval shape. Weighs 15-16 mg. Use – glaucoma. Advantage – Single application. 

3) Minidisc: Countered disc

with a convex

front and a

concave back

surface. Diameter – 4 to 5

mm. 2704/15/2023

5) Dendrimer: Dendrimers can successfully used for different routes of drug administration

and have better water-solubility, bioavailability and biocompatibility.

6) Microemulsion:

Microemulsion is dispersion of water and oil stabilized using surfactant and

co- surfactant to reduce interfacial tension and usually characterized by small

droplet size (100 nm), higher thermodynamic stability and clear appearance.

Selection of aqueous phase, organic phase and surfactant/co-surfactant systems

are critical parameters which can affect stability of the system.

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CONTROLLED DRUG DELIVERY SYSTEM FOR OCULAR THERAPY

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7) Nanosuspensions: Nanosuspension contains of pure, hydrophobic drugs (poorly water

soluble), suspended in appropriate dispersion medium. Nanosuspension technology are utilised for drug components that form

crystals with high energy content molecule, which renders them insoluble in either hydrophobic or hydrophilic media.

The bioerodible as well as water soluble/permeable polymers could be used to sustain and control the release of the medication.

The nanosuspensions can be formulated by using the quasi-emulsion and solvent diffusion method.

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CONTROLLED DRUG DELIVERY SYSTEM FOR OCULAR THERAPY

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7) Nanosuspension:

Nanosuspensions have emerged as a promising strategy for the efficient

delivery of hydrophobic drugs because they enhanced not only the rate and

extent of ophthalmic drug absorption but also the intensity of drug action

with significant extended duration of drug effect.

For commercial preparation of nanosuspensions, techniques like media

milling and high-pressure homogenization have been used.

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CONTROLLED DRUG DELIVERY SYSTEM FOR OCULAR THERAPY

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1) Nanoparticle: Nanoparticles are the particle with a diameter of less than 1μm, containing

of various biodegradable materials, such as natural and synthetic polymer, liposomes, lipids, phospholipids and even inorganic material.

The albumin nanoparticles was used to a very efficient ocular delivery system for like CMV retinitis, they are biodegradable, non-toxic and have non-antigenic effects.

nanoparticles of natural polymers which are made up of like sodium alginate, chitosan, are very effective in intraocular penetration for some specific drugs, because of contact time with corneal and conjunctival surfaces.

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PARTICULATE DRUG DELIVERY SYSTEM FOR OCULAR THERAPY

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bottle method

diffusion method

modified rotating basket method

modified rotating paddle apparatus

in vivo drug release rate study

accelerated stability studies

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EVALUATION OF OCULAR DRUG DELIVERY SYSTEM

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Jain N.K. (2010) “Advanced in Controlled And Novel Drug Delivery”. First

Edition. New Delhi. CBS Publisher and Distributor New Delhi. pp. 219-223

Collett D.M., Aulton M.E. (1996) “Pharmaceutical Practice.”First Edition.

Churchill Livingstone. Longman Group Ltd . pp. 257-270

Hiremath S.R. (2008) “A Text Book of Industrial Pharmacy, Drug Delivery

System And Cosmetic And Herbal Drug Technology”. Orient Longman Private

Ltd Chennai. pp 50-59

Kumar K.P., Bhowmik D., Harish G., Duraivel S., Pragati Kumar B. (2012)

“Ocular Insert: A Novel Controlled Drug Delivery System”. The Pharma

Innovation Journal.Vol-01(12).pp. 4-12

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REFERENCES

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Jitendra et al. Sharma P. K. Banik, A. Dixit S.(2011). “A New

Trend:“Ocular Drug Delivery System”. An International Journal Of

Pharmaceutical Sciences Vol-02(03),pp.06-18

Sharma U. K. Verma A. Prajapati S. K. PANDEY H. (2013). “Ocular Drug

Delivery: Assorted Obstruction And Contemporary Progresses”,

International Journal Of Research and Devlopment In Pharmacy .Vol-

02(03),pp.469-470

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REFERENCES

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